The broad, long-term goals of the proposed research are to understand the mechanism(s) by which peroxisome proliferating agents (PPAs) interfere with signaling cross-talk between metabolic pathways and nuclear hormone receptors producing perturbations in reproduction and development. PPAs are a structurally-diverse group of chemicals including herbicides, solvents, and plasticizers, that are known fatty acid, retinoid and endocrine disrupters. These metabolic pathways interact in the regulation of gene expression for reproduction and development. Hepatic peroxisome proliferation by PPAs has species-specificity (rats are sensitive, humans are not) but little is known about the mechanisms of PPAs endocrine disruptive effects. PPA species-specificity has recently been demonstrated in fish allowing investigation of responsive and non-responsive models. Fish exposed to PPAs can bioaccumulate these xenobiotics, and serve as biomarkers of exposure and effect. Furthermore, because human consumption of fish and fish products has increased in the last decade, it is imperative that we understand the potential for adverse effects by these contaminants. Test organisms will be a commercially-important food species, the catfish (sensitive; Haasch, 1996), and a model species, the Japanese medaka (non-sensitive; Scarano et al,. 1994). The proposed research will test the hypothesis that PPAs are endocrine disrupters producing perturbations in reproduction and development. PPAs to be investigated are: clofibrate, as a model PPA, and haloxyfop enthoxyethyl, di-n-butyl-ortho-phthalate (DBoP) and tetrachloroethylene (PCE) as environmental contaminant PPAs. Specific Aims include, 1) determining if PPA-sensitivity is ruired for endocrine disruption and if PAPAS from different chemical classes cause endocrine disruption by similar mechanisms, 2) determination of specific mechanisms of endocrine disruption by examining PPA combinations, and 3) determining if PPA-mediated endocrine disruption can be correlated with reproductive or developmental problems and if PPA exposure produces metabolic alterations in offspring. The proposed investigation will provide insight into cell signaling cross-talk between metabolic pathways and nuclear hormone receptors, endocrine disruption, and the developmental and reproductive effects of PAPAS.